Ost 2014 PLoS One

From Bioblast
Publications in the MiPMap
Ost M, Werner F, Dokas J, Klaus S, Voigt A (2014) Activation of AMPKa2 is not crucial for mitochondrial uncoupling-induced metabolic effects but required to maintain skeletal muscle integrity. PLoS One 14:e94689.

Β» PMID: 24732703

Ost M, Werner F, Dokas J, Klaus S, Voigt A (2014) PLoS One

Abstract: Transgenic (UCP1-TG) mice with ectopic expression of UCP1 in skeletal muscle (SM) show a phenotype of increased energy expenditure, improved glucose tolerance and increase substrate metabolism in SM. To investigate the potential role of skeletal muscle AMPKΞ±2 activation in the metabolic phenotype of UCP1-TG mice we generated double transgenic (DTG) mice, by crossing of UCP1-TG mice with DN-AMPKΞ±2 mice overexpressing a dominant negative Ξ±2 subunit of AMPK in SM which resulted in an impaired AMPKΞ±2 activity by 90Β±9% in SM of DTG mice. Biometric analysis of young male mice showed decreased body weight, lean and fat mass for both UCP1-TG and DTG compared to WT and DN-AMPKΞ±2 mice. Energy intake and weight-specific total energy expenditure were increased, both in UCP1-TG and DTG mice. Moreover, glucose tolerance, insulin sensitivity and fatty acid oxidation were not altered in DTG compared to UCP1-TG. Also uncoupling induced induction and secretion of fibroblast growth factor 21 (FGF21) from SM was preserved in DTG mice. However, voluntary physical cage activity as well as ad libitum running wheel access during night uncovered a severe activity intolerance of DTG mice. Histological analysis showed a progressive degenerative morphology in SM of DTG mice which was not observed in SM of UCP1-TG mice. Moreover, ATP-depletion related cellular stress response via heat shock protein 70 was highly induced, whereas capillarization regulator VEGF was suppressed in DTG muscle. In addition, AMPKΞ±2-mediated induction of mitophagy regulator ULK1 was suppressed in DTG mice, as well as mitochondrial respiratory capacity and content. In conclusion, we demonstrate that AMPKΞ±2 is dispensable for SM mitochondrial uncoupling induced metabolic effects on whole body energy balance, glucose homeostasis and insulin sensitivity. But strikingly, activation of AMPKΞ±2 seems crucial for maintaining SM function, integrity and the ability to compensate chronic metabolic stress induced by SM mitochondrial uncoupling.

β€’ O2k-Network Lab: DE Nuthetal Klaus S, DE Leipzip Ost M

Labels: MiParea: Respiration 

Organism: Mouse  Tissue;cell: Skeletal muscle  Preparation: Permeabilized tissue 

Coupling state: LEAK, OXPHOS, ET  Pathway: F, N, NS  HRR: Oxygraph-2k 

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